N-[4-cyano-3-trifluoromethyl-phenyl]-3-[4-fluorophenylsulfonyl]-2-hydroxy-2-methyl-propionamide was known as Bicalutamide in therapy.
The racemic and the optically pure Bicalutamide have antiandrogen activity. They decrease the testosterone level selectively in the prostate without influencing the regulation mechanisms of the hypothalamus (the LH-level/testosterone-level negative feedback mechanism). They have higher and more selective biological and clinical activity as compared to Flutamide {2-methyl-N-[4-nitro-3-trifluoromethyl-phenyl]-propionamide}, since they do not increase the testosterone- and the LH-level even at 19 times concentration of ED50 in the human body, while the Flutamide doubles them at 3.5 times concentration of ED50 [J. Med. Chem., 31, 954–959 (1988)]. The effect of daily 50 and 150 mg dose was tested in the clinical practice [Proc. Am. Soc. Oncology, 15, 684 (1996)]. It has been found, that in the case of primary prostate tumors the racemic Bicalutamide combined with an LHRH analog was at least as active as castration, while in the case of secondary tumors it does not substitute that.
The international patent No. WO 95/19770 describes the use of the R-(−) enantiomer. From the two enantiomers the R-(−) isomer was more active. The authors claim, that treatment with the R-(−) isomer was more advantageous, on the one hand because less substance was needed and on the other hand the R-(−) enantiomer was peripherally antiandrogen and therefor its side-effects (headache, gynecomistia, giddiness) were less pronounced, than that of the racemate.
The synthesis of racemic and optically pure enantiomers of formula (I), (Ia) and (Ib), respectively, was described in the following literature:
The patent No. EP 100172 describes the synthesis of new acylanilides by different known methods. The description contains the synthesis of compounds of formula (I), (Ia) and (Ib), too. Some of the synthetic methods disclosed in EP 100172 are described in J. Med. Chem., 31. 954–959 (1988), too.




The separation of the antipodes was described in detail in J. Med. Chem., 31, 885–887 (1988), which was also described in the patent No. EP100172.
According to the first process disclosed in EP 100172 (Method 1 hereinabove) the starting methacryl acid chloride was reacted with 4-amino-2-trifluoromethyl-benzonitrile in dimethylacetamide at 5° C. and the so obtained anilide of formula (1) was refluxed with m-chloroperbenzoic acid (MCPBA) in 1,1,1-trichloroethane in the presence of 2,5-di-tert-butyl-methylphenol (this was highly explosive). After the completion of the epoxidation reaction the formed epoxide of formula (2) was isolated. The opening of the epoxide ring of compound of formula (2) was carried out with 4-fluorothiophenol in the presence of sodium hydride, then the obtained thioether derivative of formula (II) was oxidized by known method with m-chloroperbenzoic acid in dichloromethane to yield the final product of formula (I).
According to the second process disclosed in EP 100172 (Method 2 hereinabove) the starting material was methyl methacrylate, which can be converted into epoxide only under harsh conditions (i.e. with peracetic acid in ethyl acetate at 75° C. [J. Am. Chem., 81, 680 (1959)], or with 90% hydrogen peroxide—trifluoroacetic anhydride at 40° C. [J. Am. Chem., 77, 89 (1955)], or with MCPBA in dichloromethane at ° C. in low yield [J. Med. Chem., 29. 2184 (1986)]. The epoxidation under the above mentioned conditions can be explosive. The methyl 2-methyl-oxirane-carboxylate of formula (5), which was obtained by epoxidation, was reacted with 4-fluorothiophenol in the presence of sodium hydride. The obtained methyl 2-hydroxy-2-methyl-3-(4-fluorophenylthio)-propionate of formula (6) was hydrolyzed with potassium hydroxide in aqueous ethanol over a period of 22 h to yield the 2-hydroxy-2-methyl-3-(4-fluorophenylthio)-propionic acid of formula (7), which was converted into acid chloride of formula (8) with thionyl chloride in dimethyl acetamide at −15° C. The obtained acid chloride was reacted with 4-amino-2-trifluoromethyl-benzonitrile in dimethylacetamide at −15° C. to yield the thioether derivative of formula (II), which was given in the reaction scheme of Method 1. The oxidation of the thioether derivative was carried out according to the reaction scheme of Method 1.
The starting material of the synthesis given on FIG. 3 was bromo-acetone, which was reacted according to the literature [Zh. Org. Khim., 7, 2221, (1871)] with 4-fluorothiophenol in the presence of triethylamine, the obtained thioether derivative of formula (9) was reacted with potassium cyanide under acidic conditions to yield the cyanohydrine derivative of formula (10). The 2-hydroxy-2-methyl-3-(4-fluorophenylthio)-propionic acid of formula (7) was obtained from the latter by acidic hydrolysis. The 2-hydroxy-2-methyl-3-(4-fluorophenylthio)-propionic acid of formula (7) was converted into acid chloride with thionyl chloride and the latter was transformed into amide and oxidized to yield (±)-Bicalutamide as given above.
Two procedures were known for the synthesis of the optically pure Bicalutamide:
According to one procedure [patent No. EP 100172 and J. Med. Chem., 31, 885–887 (1988)] the thioether derivative of formula (II), which was the key-intermediate of the synthesis of (±)-Bicalutamide, was synthesized, then the resolution was carried out by esterification of the hydroxyl group of the thioether derivative with optically pure R-(−)-camphoric acid chloride, the obtained diastereomers were separated by fractional crystallization or preferably by chromatography, then the optically pure esters were hydrolyzed to yield the corresponding alcohol derivatives and oxidized to give the optically pure Bicalutamide.
According to the other procedure [J. Med. Chem., 31, 885–887 (1988)], which was shown on FIG. 4, the optically pure S-(+)-Bicalutamide was obtained by asymmetric synthesis. The starting material of the synthesis was S-(+)-N-methacryloyl-proline of formula (11), which was reacted with N-bromo-succinimide in dimethyl formamide to yield the 3(S)-(bromomethyl)-3(S)-methyl-1,4-dioxo-3,4,6,7,8,8a(S)-hexahydro-l-H-pyrrolo[2,1-c][1,4]-oxazine of formula (12). The latter was hydrolyzed with hydrochloric acid to give the S-(+)-3-bromo-2-hydroxy-2-methyl-propionic acid of formula (13), which was converted into the corresponding acid chloride with thionyl chloride. The acid chloride was reacted with 4-amino-2-trifluoromethyl-benzonitrile to yield the S-(+)-N-{4-cyano-(3-trifluoromethyl)}-3-bromo-2-methyl-2-hydroxy-propionamide of formula (14). The latter was reacted with 4-fluorothiophenol in the presence of sodium hydride to give the (S)-(+)-N-[4-cyano-3-(trifluoromethyl)-phenyl]-3-[(4-fluorophenyl)-thio]-2-hydroxy-2-methyl-propionamide of formula (15), which was oxidized by known method with m-chloroperbenzoic acid to yield the optically pure S-(+)-Bicalutamide. The R-(−)-Bicalutamide can be synthesized the same way starting from R-(−)-N-methacryloyl-proline.
It was very important to examine a procedure from the point of industrial applicability, whether the procedure fulfils the following requirements:
1) The starting materials of the procedure should be easily available and as cheap as possible.
2) The use of harmful reagents should be avoided during the course of the procedure.
3) The synthesis should be safe from the point of environmental protection.
4) The formation of by-products and ballast materials, which cannot be used or processed further, should be minimized during the course of the procedure.
5) The reaction vessels generally used in pharmaceutical and chemical industry should be applicable for the realization of the synthesis.
6) It was very important, that the synthesis should give pure final product, which does not need further, expensive purification.
All of the syntheses described in the literature apply steps, which do not fulfil one or other of the above conditions.
According to Method 3 disclosed hereinabove the synthesis of cyanohydrine derivative of formula (10) and its further reaction under acidic conditions was dangerous for health. The hydrolysis of the cyanohydrine in the presence of concentrated hydrochloric acid at 110° C. or with hydrochloric acid in acetic acid requires special equipment. The use of sodium hydride in tetrahydrofuran was an inflammable step. In the second step (epoxidation) of the first procedure the oxidation was carried out with m-chloroperbenzoic acid. This oxidation step, which was carried out at high temperature (i.e. at 120° C.), was explosive.
The known procedures, which were carried out only on few-gram-scale, can lead to further, unexpected problems during the industrial realization. (i.e. an oxidation carried out in a few m3 reactor can easily ‘run over’, resulting in an explosion; weighing and adding a large quantity of sodium hydride needs special attention, etc.)
The modern requirements of pharmacopoeia specify numerous analyzing methods, i.e. thin layer or liquid chromatographic content determination, moreover fix and limit the number and the quantity of the impurities, therefor it was a basic requirement, that the product formed during the synthesis should contain the least impurities possible.